: The long-term objective of this research is to develop working oligonucleotide based tools (OBTs) that control via an "antisense" strategy the replication of HIV and viruses associated with HIV infections (hepatitis, herpes, and papillomaviruses). This work will prepare OBTs that bear functional groups that catalyze the hydrolysis of semi-complementary messenger RNA molecules. The work will be guided by an understanding of the catalytic mechanism of RNase A, developed by site-directed mutagenesis studies in these laboratories with RNase A itself. The catalytic OBTs will incorporate guanosine derivatives carrying imidazole-amine units tethered to the 2-position exocyclic amino group, pyrimidine bases carrying functional groups at the 5-position, and selected mismatches. A combinatorial chemistry program will then be used to optimize the catalytic activity of these OBTs. The ability of all of these OBTs to cleave semicomplementary oligonucleotides in vitro will be tested. These will then be appended to the backbone that, at the time that the experiments are done, has the best chance of bringing these catalytic groups into a cell.